Molecular genetics Flashcards
What steps of the cell cycle constitute interphase
All except mitosis i.e. G0, G1, S & G2
In interphase the genetic material and organelles of the cell duplicate
The chromatids (half of chromosome that we get from each parent) duplicate and are joined together at nucleus:
- 46 chromosomes become 92 chromatids
Outline the stages of mitosis
Prophase:
- Chromatids condense
- Spindle fibres form
Metaphase:
- Nucleus breaks down
- Spindle fibres attach to each chromatid and they line up at equator of cell (metaphase plate)
Anaphase:
- The chromosomes separate into chromatids through the shortening of spindle fibres dividing the centromeres
- Aligned at opposites of the cells
Telophase:
- New nuclear membrane forms around each set of chromosomes
- Spindle fibres split down
- Cytokinesis - the cell membrane splits via pinching into two separate cells separating each set of chromatids
Outline the stages of mitosis
Prophase:
Metaphase
Anaphase
Telophase
How does meisosis differ to mitosis?
In mitosis cells divide to form two daughter cells each with same amount of chromosomes as the parent (46)
In meiosis cells divide to form 4 daughter cells with half the amount of chromosomes as the parent (23):
- The process involves the same prophase, metaphase, telophase and cytokinesis however this happens twice
- The first time round in interphase rather than chromatids duplicating and attaching at centromeres whole new chromosomes are produced
- Therefore in the first metaphase M1 these line up side by side –> when anaphase splits them and telophase forms a ring around the new cells each has the same amount of DNA as at the start
- A seconds P2,M2, T2 and cytokinesis then occurs dividing the genetic material by half
What is crossing over?
Occurs in prophase 1 of meisosis - ends of sister chromosomes may overlap at similar genes positions sharing DNA to form recombinant chromosomes
What do the numbers 1, 2, 3 , 4 represent
1 - telomere
2 - centromere
3 - p i.e. short arm of chromosome
4 - q i.e. long arm of chromosome
What is a metacentric vs acrocentric/submetacentric chromosome?
Metacentric chromosome - centromere is at the centre (i.e p and q arms are equal length)
Acrocentric/submetacentric - centromere is at one end
Other types of chromosome (telocentric and holocentric) are not seen in humans
What name is given to cells with the incorrect number of chromosomes?
Aneuploid cells
- Aneuploidy can occur from extra number or one chromosome (trisomy 21 for example) or rarely if total chromosome number multiples (triploidy or tetraploidy) however the later to cause spontaneous abortion
How does trisomy/monosomies arises?
From non-disjunction during meisosis - a failure of the chromatids/chromosomes to separate
This can lead to one gamete having double the sets of one chromosome than it should - produces trisomy OR the gamete may have no set of one chromosome - produces monosomy
Moasiacism occurs when the non-disjunction occurs in mitosis after the gametes fuse - this causes the production of two cell lineages (with and without trisomy) leading to milder symptoms
Only trisomy 21 survives into adulthood, trisomies 13 and 18 often die in childhood
What are the genetic abnormalities of
a) Downs syndrome
b) Turners syndrome
c) Pataus syndrome
d) Edwards syndrome
e) Metafemale
a) Trisomy 21
b) Turner’s syndrome - single X chromosome 45X
c) Trisomy 13
d) Trisomy 18
e) Trisomy X chromosome
What are the gestational signs of down’s?
Reduced alpha feto protein
Increased bHCG
A single nuchal fold on USS
Outline some clinical signs of downsyndrome?
Prominent epicanthal folds
Single palmar crease
Low set ears
Intellectual disability
Hypothyroidism
Heart abnormalities (ASD)
How does Edward’s syndrome present?
More common in girls > boys
Rocker bottom feet
Low set ears
Severe intellectual disability
Small jaw (microganthia)
Congenital heart disease
Clenched hands
Prominent occiput
Widely spaced eyes
Overlapping fingers
How does Patau’s syndrome present?
Microcephaly
Microphthalmia
Cleft lip/palate
Polydactyly
Colomba eye
Intellectual disability
Abnormal forebrain structure
How does Turner’s syndrome present?
Short stature
Webbed neck
Low hairline
Retrognathism (posterior position of mandible)
Disharmonic IQ profile - normal verbal, reduced performance.
Usually only X is maternal in origin (80%) if paternal then better IQ.
This differs to other syndromes described where often aneuploidy arises in the maternal gamete
What is a nucleoside?
A molecule made of a nitrogenous base and a pentose sugar - when phosphorylated they are nucleotides - the components of nucleic acid
What is DNA made of?
Deoxyribose-phosphate backbone and bases of nucleic acid - two stands joined together by hydrogen bonds
Bases can be purines (Adenosine or Guanine) or pyrimidine (Thymine or Cystosine)
How many base pairs make a codon?
3 - each codon indicates a specific amino acid. There are 20 amino acids. 10 are essential and are not derived from food but need to be synthesised within the body
What are protein coding regions
Name two type of introns sequences
Interspersed:
- Long interspersed
- Short interspersed
TANDEM REPEATs:
Satelite:
- Large series of repeats
Microsatelite - telomeric repeats (chromosomal integrity)
- hypervariable repeats (DNA finger-printing)
Minisatelite - single, di or trinucleotide repeats
What does hnRNA refer to?
What does hnRNA refer to?
Heterogenous nuclear RNA - RNA that contains non codon regions (introns)
Splicing is the process that removes these regions resulting in messenger RNA that leaves the nucleus
What do nucleosomes do?
Nucleosomes remove non-coding RNA from hnRNA to produce mRNA
Where are ribosomes found?
In the cytoplasm attached to rough endoplasmic reticulum
Name the 3 stages of translation
Initiation - methionine containing tRNA binds to the polpeptide P site of the Ribosome
Elongation - at the aminoacyl A site each new tRNA binds (with attached amino acids bind). Amino acids are bound 1 by 1
Termination - termination sequence UAG, UAA or UGA signals end of protein
Modification is extra post translation changes that occur to the protein before it becomes functionally active. This occurs in the ER or golgi bodies - it can occur spontaneously as translation occurs
What is aminoacyl-tRNA synthetase?
The enzyme that binds tRNA to specific amino acids in the presence of Mg2+
What is translocation
A reciprocal exchange of genetic material between 2 chromosomes
In Robertsonian translocation exchange is not reciprocal and from 2 chromosomes the p arms are lost and one metacentric chromosome is formed.
i.e from one 14 and one 21 - produces 14/21 (alongside remaining 14 and remaining 21)
- When meisosis gametes formed can contain 14/21 and 21 –> produce trisomy 21 during fertilisation
- OR gamete may only have one 14 or 21 –> monosomy 14 or monosomy 21
Robertsonian translocation accounts for 4% of downs
Robertsonian translocation chromosome can be inherited from either parent
Outline the genetic abnormalities and brief symptoms associated with
a) DiGeorge (Velocardiofacial)
b) William Syndrome
c) Smith Magnesis Syndrome
d) Angelmann Syndrome
e) Prader Willi
f) Cru-di-Chat
a) 22q.11.2 autosomal dominant - 25% get psychosis, mild to moderate LD, facial deformity including cleft palate, absent or malformed parathyroid (hypocalcaemia), articulatory problems, broad nasal bridge
b) 7.11 microdeletion - hypercalcium, supravalvular aortic stenosis, speech superficially fluent, mild-moderate LD, disinhibited, hyperacusis
c) 17.11.2 microdeletion - mild-moderate self-harm, pulling off nails, sleep disturbances and hugging, inserting of foreign objects, moderate to severe LD
d) 15q11-13 maternal deletion - developmental delay, low IQ, jerking movements and hand flapping
e) 15q11-13 deletion - obesity, small stature, decreased IQ, skin picking, hyperphagia - small gonads
f) 5p chromosome deletion (locus 5p.15.2) - small facial features (poorly developed), cat-like cry, feeding difficulties
Name the 3 mendelian laws
Law of uniformity - the offspring must inherent either trait from each parent
Principle of segregation - only one allele from each parent passes to the child and is from pure chance - the parental alleles separates during meiosis. Thus if A and B alleles with Mother AB and Father AB child can be AA, BB or AB
Independent assortment - different traits do not depend on each other
Outline how the risk of Schizophrenia varies in the following
a) General population
b) First cousin
c) Aunt/Uncle
d) Niece/nephew
e) Grandchildren
f) Parent
g) Half sibling
h) Full sibling
i) Children
j) Fraternal twins (non-identical)
k) Off spring of parents with Schz
l) Identical twins
a) General population 1%
b) First cousin 2%
c) Aunt/Uncle 2%
d) Niece/nephew 4%
e) Grandchildren 5%
f) Parent 6%
g) Half sibling 6%
h) Full sibling 9%
i) Children 13%
j) Fraternal twins (non-identical) 17%
k) Off spring of parents with Schz 46%
l) Identical twins 48%
If there is a mutation affecting the transcriptional activity of a new gene it is likely to affect?
The promoter region of the gene - the area of DNA that RNA polymerase binds to in order to begin mRNA synthesis from DNA
What are the 5 conditions that need to be met to ensure Hardy-Weinberg Equilibrium
a) No mutations
b) No loss or gain of genetic info
c) Random mating
d) Population is large enough to ensure no genetic drift - i.e. random chance of geneotype or allelic frequency changing
e) No natural selection - i.e. a genotype or allele cannot confer a survival advantage
What is the Hardy-Weinberg Equation
p2 + 2pq + q2 = 1
p2 (autosomal dominant)
2pq (heterozygous)
q2 (autosomal recessive)
What type of analysis determines the method of inheritance using family data?
Segregation analysis
What is linkage analysis
A method that identifies a piece of DNA of known location that is present in affected individuals (inherited) but not unaffected individuals
- from here the disease gene must be close
Lyonisation is the process where…
One of the X chromosomes is made inactivated to prevent a toxic double dose of x-linked genes.
The x-chromosome made inactive is called a Barr body
This condition results in multiple non-malignant tumours growing in the brain and body of an individual?
Tuberous sclerosis - implicated genes are TSC1 and TSC2
Psychiatric co-morbidities include Autism, ADHD, Anxiety and Psychosis
Seizures, developmental delay and skin lesions
It is autosomal dominant with variable expression but 95% penetrance
Name some diseases with mitochondrial inheritance
Leber’s hereditary optic neuropathy
Kearn’s Sayre syndrome
Name an anagram to remember DiGeorge Syndrome
Cardiac abnormalites
Abnormal faces
Thymic aplasia - recurrent infections
Cleft palate
Hypocalcaemia/Hypercalcaemia
2
2
What are the trinucleotide repeats seen in
a) Huntington’s
b) Fragile X syndrome
c) Muscular dystrophy
d) Friedrich’s ataxia
a) CAG
b) CGG
c) CTT
d) gAA
What are the symptoms of fragile X syndrome and what gene is affected?
Affects FMR1 gene - CGG repeats at exon sites (FRAXA, FRAXE, FRAXF)
If > 52 repeats - destablisation during spermatogenesis or oocytogenesis and expansion occurs
Clinical symptoms if > 200 repeats:
- Men - large testes, lower IQ, prominent ear lobes, high pitch voice and mental retardation
- Women -> mild LD, early menopause
If 55-200 then premutation:
- Men –> intention tremor and ataxia later in life
- Women –> premature ovarian failure and cognitive/behavioural difficulties
- Shows anticipation
What chromosome is Huntington’s expressed on?
Chromosome 4 - 4p16.3 - a trinucleotide repeat of CAG here (40-55)
Unlike x-linked diseases here if paternal mutation inherited - there is greater repeats and anticipation (in x-linked diseases tends to be if maternal gene then greater anticipation)
What mechanism is responsible for genomic imprinting?
DNA methylation
Parent of origin phenomenon - i.e. where it matters if gene inherited from mother or dad which syndrome occurs
Prader Willi 15q11-13 - paternally inherited (20% of cases come from maternal uniparental disomy - i.e. both copies from mum)
Angelman Syndrome 15q11-13 matrernally inherited (only 4% of cases are from paternal uniparental disomy)
Outline how the following disorders are inherited and briefly their symptoms:
a) Tuberous Sclerosis
b) Treacher Collins Syndrome
c) Apert syndrome
d) Noonan syndrome
e) Hurler syndrome
f) Lesch-Nyan syndrome
a) Auto Dominant but most spontaneous 9q34/16p13 - Ash leaf macules, brain hamartomas, mental retardation, adenoma sebaceum, heart and kidney cysts
b) Auto dominant 5q31 - down slanting eyebrows, maxo/mandibular hypoplasia, malformed pinna, moderate LD
c) Auto dominant 10q - craniosynostosis (fusing of skull), mitten hands, trapezoid mouth, variable LD
d) Autosomal dominant - Chr 12 - LD, cryptorchidism, pulmonary stenosis, webbed neck, short stature
e) Autosomal recessive 4p16 - corneal oedema, deteriorating IQ after age 2, joint stiffness and coarse features
f) Xq26-27. X-linked recessive - affects enzyme HGPRT. Presents with poor muscle control, self-mutilating behaviours, gout (hyperuricaemia and hyperuricosuria). Can present at any time
